ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive disease that can lead to right heart failure and death. This devastating disease poses a large financial impact, since medications are expensive and most patients die in a hospital setting. Currently, there are limited biomarkers to help understand the pathobiology of the disease and no mechanistic tools to guide treatment selection. We know little on the interaction between the pulmonary and extrapulmonary vasculatures. Based on our preliminary data, we hypothesize that: (i) the extrapulmonary (cutaneous) microvasculature in IPAH will provide a non-invasive approach of assessing the pulmonary circulation and allow us to test major putative signaling pathways; (ii) defects may manifest at different points along the nitric oxide (NO) and prostacyclin (PGI2) signaling pathways in IPAH patients, and contribute to the extrapulmonary microvascular dysfunction. Aim 1: To study the link between the pulmonary and extrapulmonary circulations and identify the mechanisms involved in the extrapulmonary vascular dysfunction in IPAH. Aim 2: To challenge the extrapulmonary microvasculature in patients with IPAH to predict response to therapy. Our preliminary data, obtained at the time of the diagnostic right heart catheterization, demonstrated a global vascular involvement in IPAH and suggested that the pulmonary and extrapulmonary circulations have a uniform response to vasoactive challenges. We found an association between abnormalities of the NO pathway in plasma and platelets of patients with IPAH and the cutaneous microvascular response to vasoactive agents. The responses to acetylcholine (tests the NO pathway) and treprostinil (tests the PGI2 pathway) iontophoresis predict long-term response to phosphodiesterase-5 inhibitors and PGI2 analogues, respectively. We identified 3 phenotypes of IPAH patients based on the response to vasoactive agents. We propose to test the reactivity of the pulmonary circulation to inhaled NO, the response of the extrapulmonary microvasculature to vasoactive stimuli that challenge the NO and PGI2 pathways, and determine the expression and activity of soluble guanylate cyclase in platelets of IPAH patients. These tests will allow us to phenotype IPAH patients based on the putative mechanisms of the disease; a critical need as expressed in the NHLBI-strategic plan for lung vascular research. The results of this novel proposal will advance the understanding of the pathobiology of IPAH, define the link between the pulmonary and extrapulmonary circulations and predict response to PAH-specific therapies. The in-vivo testing of the NO and PGI2 pathways will help guide PAH treatment based on mechanistic data. It is our conviction that this innovative and non-invasive approach has the potential to revolutionize the way we currently manage and treat this ominous disease.